WO2004020442A1 - Selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders - Google Patents

Selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders Download PDF

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WO2004020442A1
WO2004020442A1 PCT/US2003/026878 US0326878W WO2004020442A1 WO 2004020442 A1 WO2004020442 A1 WO 2004020442A1 US 0326878 W US0326878 W US 0326878W WO 2004020442 A1 WO2004020442 A1 WO 2004020442A1
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compound
alkyl
hydrogen
aryl
group
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PCT/US2003/026878
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English (en)
French (fr)
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Wen-Lian Wu
Duane A. Burnett
William J. Greenlee
Thavalakulam K. Sasikumar
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Schering Corporation
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Priority to AU2003262926A priority Critical patent/AU2003262926A1/en
Priority to MXPA05002249A priority patent/MXPA05002249A/es
Priority to JP2004531584A priority patent/JP4555685B2/ja
Priority to EP03791865A priority patent/EP1537115B1/en
Priority to CA2495879A priority patent/CA2495879C/en
Priority to DE60321354T priority patent/DE60321354D1/de
Publication of WO2004020442A1 publication Critical patent/WO2004020442A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to bioisostere heterocycles useful as D 1 /D 5 receptor antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat obesity, metabolic disorders and CNS disorders.
  • Substances, which are administered to reduce craving should not produce significant physiological effects, such as stimulation of mood or elevate blood pressure or heart rate. This could result in the substitution of one abused substance for another. Compounds which dampen the desire for the abused substance, also should not exacerbate the physiological symptoms of the abused substance in the event the individual relapses and takes the abused substance. Substances administered to reduce craving also should not produce significant adverse effects, such as dysphoria, restlessness or stiffness.
  • CNS central nervous system
  • OCD Obsessive-compulsive disorder
  • OCD is characterized by anxiety-provoking and intrusive thoughts (e.g., fear of contamination and germs, doubt and uncertainty about future harm, need for symmetry, etc.), which lead to ritualistic and/or irrational behavior (e.g., constant checking, washing, touching, counting, etc.).
  • anxiety-provoking and intrusive thoughts e.g., fear of contamination and germs, doubt and uncertainty about future harm, need for symmetry, etc.
  • ritualistic and/or irrational behavior e.g., constant checking, washing, touching, counting, etc.
  • Somatoform disorders are characterized by abnormal preoccupation with one's appearance or physical condition.
  • body dysmorphic disorder is a preoccupation with an imagined or slight defect in appearance.
  • Many sufferers of body dysmorphic disorder are severely debilitated by their abnormal preoccupation, with significant impairment in social, occupational, or other important aspects of daily life. See Phillips, J. Clin. Psychiatry 57 (suppl. 8), pp. 61-64 (1996).
  • Hypochondriasis is characterized by a persistent conviction that one is, or is likely to become ill. Many hypochondriacs are unable to work or engage in ordinary activities due to their preoccupation with illness.
  • Dissociative disorders are characterized by sudden temporary alterations in identity, memory, or consciousness, segregating normally integrated memories or parts of the personality from the dominant identity of the individual.
  • Depersonalization disorder which is a dissociative disorder, is characterized by one or more episodes of depersonalization (feelings of unreality and strangeness in one's perception of the self or one's body image).
  • Eating disorders e.g., anorexia nervosa, bulimia, and binge eating
  • Eating disorders are characterized by abnormal compulsions to avoid eating or uncontrollable impulses to consume abnormally large amounts of food. These disorders affect not only the social well-being, but also the physical well-being of sufferers.
  • Impulse control disorders e.g., pathological gambling, compulsive buying, sexual compulsions and kleptomania
  • Trichotillomania is a habitual hair pulling that usually appears in children. See Merck Index, 15 th Edition (1987); Christenson, Gary; O'Sullivan, Richard, Trichotillomania: Rational treatment options, CNS Drugs (1996), 6(1 ), 23-34; Tukel R; Keser V; Karali N T; Olgun T O; Calikusu C, Comparison of clinical characteristics in trichotillomania and obsessive-compulsive disorder, JOURNAL OF ANXIETY DISORDERS (2001 Sep-Oct), 15(5), 433-41 ; du Toit P L; van Kradenburg J; Niehaus D J; Stein D J, Characteristics and phenomenology of hair-pulling: an exploration of subtypes, COMPREHENSIVE PSYCHIATRY (2001 May-Jun), 42(3), 247-56.
  • Autism is a disorder characterized by a preoccupation with one ' s own self and a severe impairment of the ability to perceive or react to outside stimuli in a normal fashion. Many autistics are incapable of even communicating with others.
  • the present invention provides a novel class of bioisostere heterocycles as D-1/D5 receptor antagonists, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical compositions or formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of obesity, metabolic disorders, CNS disorders or one or more diseases associated with obesity using such compounds or pharmaceutical compositions.
  • the present application provides a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula I:
  • G is hydrogen, halo, alkyl, alkylthio, nitro, nitrile, hydroxy, alkoxy, alkylsulfinyl, alkylsulfonyl, trifluoromethyl or trifluromethoxy;
  • V is -CH 2 -;
  • X is selected from the group consisting of CH, C(alkyl), CCF 3 and N;
  • Y is selected from the group consisting of CH, C(alkyl) and N;
  • R is hydrogen, alkyl, allyl, cycloalkyl or cycloalkyl(alkyl);
  • R 2 is hydrogen or 1 to 4 substituents which can be the same or different, each
  • R 3 is aryl, R 10 -substituted aryl, arylalkyl, heteroaryl, alkyl or hydrogen;
  • R 4 is aryl, R 10 -substituted aryl, heteroaryl, alkyl or hydrogen, or R 3 , R 4 and N of -NR 3 R 4 together can be joined together to form a ring selected from the group consisting of azetidine, R 8 -substituted azetidine, pyrrolidine, R 8 -substituted pyrrolidine, piperidine, R 8 -substituted piperidine, piperazine, R 8 -substituted piperazine, morpholine and R 8 -substituted morpholine;
  • R 5 is alkyl, arylalkyl, -C(O)NR 3 R 4 , -S(O) 2 NR 3 R 4 , -S(0) 2 R 8 , -C(O)R 8 , -C(O)OR 8 or -R 9 O-alkyl;
  • R 6 is hydrogen, alkyl, aryl, R 0 -substituted aryl, heteroaryl or arylalkyl, or R 5 , R 6 and N in -NR 5 R 6 together can be joined together to form a ring selected from the group consisting of azetidine, R 8 -substituted azetidine, pyrrolidine, R 8 -substituted pyrrolidine, piperidine, R 8 -substituted piperidine, piperazine, R 8 -substituted piperazine, morpholine and R 8 -substituted morpholine;
  • R 7 is hydrogen, alkyl, aryl or arylalkyl
  • R 8 is hydrogen, aryl, alkyl, arylalkyl or heteroaryl
  • R 9 is hydrogen, alkyl, aryl, R 10 -substituted aryl, heteroaryl or arylalkyl
  • R 10 is selected from the group consisting of aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, Y ⁇ Y 2 N-, Y ⁇ N-alkyl-, Y 1 Y 2 NC(O)- and Y ⁇ NSO ⁇ , wherein Y ⁇ and Y 2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl;
  • R 11 is hydrogen, alkyl or arylalkyl
  • R 12 is -C(O)R 13 , -S(O) 2 R 13 , -C(O)NR 3 R 4 or -C(O)OR 13 ;
  • R 13 is alkyl, aryl, R 10 -substituted aryl, heteroaryl or arylalkyl.
  • the present application provides a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula II:
  • formula II wherein p is 0, 1 or 2 and when p is 0, the carbons to which (V) p is shown connected are not linked to each other but are linked to hydrogen;
  • G is hydrogen, halo, alkyl, alkylthio, nitro, nitrile, hydroxy, alkoxy, alkylsulfinyl, alkylsulfonyl, trifluoromethyl or trifluromethoxy;
  • V is -CH 2 -;
  • W is selected from the group consisting of O, S NH and N(alkyl);
  • Z is selected from the group consisting of NH, N(alkyl), S and O;
  • R 1 is hydrogen, alkyl, allyl, cycloalkyl or cycloalkyl(alkyl);
  • R 3 is aryl, R 10 -substituted aryl, arylalkyl, heteroaryl, alkyl or hydrogen;
  • R 4 is aryl, R 10 -substituted aryl, heteroaryl, alkyl or hydrogen, or R 3 , R 4 and N of -NR 3 R 4 together can be joined together to form a ring selected from the group consisting of azetidine, R 8 -substituted azetidine, pyrrolidine, R 8 -substituted pyrrolidine, piperidine, R 8 -substituted piperidine, piperazine, R 8 -substituted piperazine, morpholine and R 8 -substituted morpholine;
  • R 5 is alkyl, arylalkyl, -C(O)NR 3 R 4 , -S(O) 2 NR 3 R 4 , -S(O) 2 R 8 , ⁇ -C(O)R 8 , -C(O)OR 8 or -R 9 O-alkyl
  • R 6 is hydrogen, alkyl, aryl, R 10 -substituted aryl, heteroaryl or arylalkyl, or R 5 , R 6 and N in -NR 5 R 6 together can be joined together to form a ring selected from the group consisting of azetidine, R 8 -substituted azetidine, pyrrolidine, R 8 -substituted pyrrolidine, piperidine, R 8 -substituted piperidine, piperazine, R 8 -substituted piperazine, morpholine and R 8 -substituted morpholine; R 7 is hydrogen, alkyl
  • R 13 is alkyl, aryl, R 10 -substituted aryl, heteroaryl or arylalkyl.
  • the compounds of formulae I and II can be useful as D 1 /D 5 receptor antagonists and can be useful in the treatment of CNS disorders, metabolic disorders such as obesity and eating disorders such as hyperphagia.
  • Another embodiment of this invention is directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formulae I or II, or a pharmaceutically acceptable salt of said compounds, and a pharmaceutically acceptable carrier therefore.
  • the present invention provides compounds which are represented by structural formulae I and II, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.
  • G is halo
  • R 1 is hydrogen, alkyl, cyclopropyl or cyclopropylmethyl and R 2 is hydrogen.
  • G is chloro.
  • R 1 is hydrogen or methyl.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain, which may be straight or branched.
  • substituted alkyl means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(0)O-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least one nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxali ⁇ yl, phthalazinyl, imidazo[1 ,2-a]pyhdinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 3 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkylalkyl group.
  • suitable cycloalkylalkyl groups include cyclopropylmethyl and cyclopropylethyl.
  • the bond to the parent moiety is through the alkyl.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
  • Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
  • Ring system substituent means a substituent attached to an aromatic or non- aromatic ring system, which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, Y ⁇ Y 2 N-, Y ⁇ Y 2 N-alkyl-, Y 1 Y 2 NC(0)- and Y 1
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, pyrrolidonyl, tetrahydrothiophenyl, and the like.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3- ylmethyl. The bond to the parent moiety is through the alkyl. "Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined.
  • Preferred hydroxyalkyls contain lower alkyl.
  • suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylsulfinyl means an alkyl-S(O)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(0 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formulae I and II or a salt and/or solvate thereof.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in antagonizing the dopamine receptor and thus producing the desired therapeutic, ameliorative or preventative effect.
  • salts can form salts, which are also within the scope of this invention.
  • Reference to the compounds of formulae I and II herein is understood to include reference to salts thereof, unless otherwise indicated.
  • compounds of formulae I and II contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwittehons (“inner salts”) may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the formulae I and II may be formed, for example, by reacting a compounds of formulae I and II with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
  • Compounds of formula I and II can have reduced potency at the Cytochrome P450 2D6 receptor and therefore can have reduced potential for affecting the metabolism of other drugs.
  • Compounds of formula I and II can be highly selective, high affinity D-1/D5 receptor antagonists useful for the treatment of obesity.
  • Another aspect of this invention is a method of treating a patient (e.g., human) having a disease or condition therapeutically treated by administering a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate, of said compound to the patient.
  • a patient e.g., human
  • a pharmaceutically acceptable salt or solvate of said compound
  • a useful dosage is about 0.001 to 100 mg/kg of body weight/day of the compound of formula I or II.
  • a preferred dosage is about 0.01 to 25 mg/kg of body weight day of a compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Another aspect of this invention is directed to a method of treating obesity comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Another aspect of this invention is directed to a method for treating eating and metabolic disorders such as bulimia or anorexia comprising administering to a patient a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a patient a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a patient a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Another aspect of this invention is directed to a method for treating type II diabetes comprising administering to a patient a therapeutically effective amount of at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate of said compound.
  • the compounds of this invention are expected to be useful in the therapy of a patient suffering from obsessive compulsive disorder, a somatoform disorder, a dissociative disorder, an eating disorder, an impulse control disorder, or autism by administering an effective amount of a compound of formula I or II or salt or solvate thereof.
  • the compounds of formulae I and II can be useful in the treatment of a variety of eating disorders including (but not limited to) anorexia nervosa, bulimia, and binge eating.
  • Compounds of formulae I and II can be useful in the treatment of a variety of impulse control disorders including (but not limited to) pathological gambling, trichotillomania, compulsive buying, and sexual compulsion.
  • Another aspect of this invention is a method for treating obesity comprising administering to a patient (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate; and b. an amount of a second compound, said second compound being an anti- obesity and/or anorectic agent such as a ⁇ 3 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist wherein the amounts of the first and second compounds result in a therapeutic effect.
  • a patient e.g., a female or male human
  • an amount of a first compound said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate
  • an anti- obesity and/or anorectic agent such as a ⁇ 3 agonist, a thyromimetic agent, an anoretic
  • This invention is also directed to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a. a first compound, said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate; and b. a second compound, said second compound being an anti-obesity and/or anorectic agent such as a ⁇ 3 agonist, a thyromimetic agent, an anoretic, or an NPY antagonist; and/or optionally a pharmaceutical carrier, vehicle or diluent.
  • a kit comprising: a.
  • Preferred anti-obesity and/or anorectic agents in the above combination methods, combination compositions and combination kits include: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as "leptin”), a leptin analog, a leptin receptor agonist, a gal
  • anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.
  • Another aspect of this invention is a method treating diabetes comprising administering to a patient (e.g., a female or male human) a. an amount of a first compound, said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate; and b.
  • a second compound said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1 B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.
  • a second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1 B inhibitor, a dipeptidyl protease
  • This invention is also directed to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1 B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR- gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally a pharmaceutical carrier, vehicle
  • kits comprising: a. an amount of a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form; b.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any methods known to the art for the manufacture of pharmaceutical compositions .
  • compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients include without limitation, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as com starch, or alginic acid; binding agents such as starch, gelatin, or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl diasterate may be employed. They may also be coated by the technique described in U.S. Pat. Nos. 4,256,108; 4, 166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of such suspensions.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia.
  • Dispersing or wetting agents may be a naturally occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate.
  • a naturally occurring phosphatide such as lecithin
  • condensation products of an alkylene oxide with fatty acids for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin, aspartame or the like.
  • preservatives for example, ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example, ethyl or n-propyl p-hydroxybenzoate
  • flavoring agents for example, ethyl or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose, saccharin, aspartame or the like.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of formulae I and II or their pharmaceutical compositions are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds of formulae I and II or their pharmaceutical compositions can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds or the pharmaceutical compositions of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of formulae I and II or their pharmaceutical compositions of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compounds of structural formulae I and II useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to 500 mg/kg of bodyweight. The range is more particularly from about 0.01 mg/kg to 150 mg/kg of body weight per day or most particularly 0.01 mg/kg to 10 mg/kg.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • Procedure D A mixture of 8.5 g of pyridine and 10 mL of concentrated HCl was distilled at
  • Compound 12B and 12C can be prepared analogously.
  • Compound 14B and 14C can be prepared analogously.
  • Compound 23B can be prepared analogously.
  • the compounds of the present invention exhibit D 1 /D 5 receptor antagonizing activity, which has been correlated with pharmaceutical activity for treating CNS disorders such as OCD, trichotillomania, metabolic disorders such as obesity, eating disorders such as hyperphagia, and diabetes. This utility is manifested by activity in the following assay.
  • Affinity values (Ki) of compounds at human D and D 2 receptors were ascertained using radioligand binding competition assays.
  • Ltk- cells expressing Di and D 2 (long variant) receptors were lysed in hypotonic buffer for membrane preparation.
  • Membranes were incubated with various concentrations of test compound and 1 nM [3H] of a compound of formula III and 0.2 nM [3H] Methylspiperone for Di and D 2 assays, respectively.
  • Non-specific binding was defined as binding in the presence of 10 micromolar of a compound of formula III for Di assays and 10 micromolar butaclamol for Di assay ' s.
  • bound radioligand was separated from free by rapid filtration. Bound radioactivity on the dried filters was quantified by liquid scintillation counting.
  • Ki values for D-i and D 2 assays for the instant compounds are shown in Table 1.
  • a range of Di receptor binding activity (Ki values) of from about 5 nM to about 2000 nM was observed.
  • a range of D 2 receptor binding activity (Ki values) of from about 200 nM to about 10000 nM was observed.
  • Compounds of this invention preferably have a D-i binding activity in the range of from about 5 nM to about 100 nM, more preferably from about 5 to about 50 nM, and most preferably from about 5 to about 20 nM.

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AU2003262926A AU2003262926A1 (en) 2002-08-29 2003-08-27 Selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders
MXPA05002249A MXPA05002249A (es) 2002-08-29 2003-08-27 Antagonistas selectivos del receptor d1/d5 para el tratamiento de obesidad y trastornos del sistema nervioso central.
JP2004531584A JP4555685B2 (ja) 2002-08-29 2003-08-27 肥満およびｃｎｓ障害の処置のための選択的ｄ１／ｄ５レセプターアンタゴニスト
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WO2005035504A2 (en) * 2003-05-22 2005-04-21 Schering Corporation 5-h -benzo [d] naphth [2, 1-b] azepine derivative as selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders

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EP0230270A2 (en) * 1986-01-16 1987-07-29 Schering Corporation Fused benzazepines
EP0351733A1 (en) * 1988-07-18 1990-01-24 Schering Corporation Use of 2,3,4,5-tetrahydro-1H-3-benzazepines in the treatment of neurological disorders
WO2003006466A1 (en) * 2001-07-13 2003-01-23 Pharmacia & Upjohn Company Hexahydroazepino (4, 5-g) indoles and indolines as 5-ht receptor ligands

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EP0363353B1 (en) * 1987-07-15 1992-07-22 Schering Corporation Fused benzazepines
DK325188D0 (da) * 1988-06-15 1988-06-15 Novo Industri As Hidtil ukendte benzazepinderivater

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EP0230270A2 (en) * 1986-01-16 1987-07-29 Schering Corporation Fused benzazepines
EP0351733A1 (en) * 1988-07-18 1990-01-24 Schering Corporation Use of 2,3,4,5-tetrahydro-1H-3-benzazepines in the treatment of neurological disorders
WO2003006466A1 (en) * 2001-07-13 2003-01-23 Pharmacia & Upjohn Company Hexahydroazepino (4, 5-g) indoles and indolines as 5-ht receptor ligands

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035504A2 (en) * 2003-05-22 2005-04-21 Schering Corporation 5-h -benzo [d] naphth [2, 1-b] azepine derivative as selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders
WO2005035504A3 (en) * 2003-05-22 2005-06-30 Schering Corp 5-h -benzo [d] naphth [2, 1-b] azepine derivative as selective d1/d5 receptor antagonists for the treatment of obesity and cns disorders

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